Human genetic studies have revealed rare missense and protein-truncating variants in GRIN2A, encoding for the GluN2A subunit of the NMDA receptors, that confer significant risk for schizophrenia (SCZ). Mutations in GRIN2A are also associated with epilepsy and developmental delay/intellectual disability (DD/ID). However, it remains enigmatic how alterations to the same protein can result in diverse clinical phenotypes. Here, we performed functional characterization of human NMDA receptors (GluN1/GluN2A heteromers) that contain SCZ-linked GluN2A variants, and compared them to NMDA receptors with GluN2A variants associated with epilepsy or DD/ID. All tested protein-truncating variants and a subset of missense variants associated with SCZ led to a loss-of-function (LoF) phenotype, whereas epilepsy and DD/ID-associated variants resulted in both gain-and loss-of-function phenotypes. We additionally show that M653I, a LoF GRIN2A variant associated with DD/ID, exerts a dominant-negative effect when co-expressed with a wild-type GluN2A, whereas Y698C, a LoF SCZ-linked variant, does not. These findings demonstrate that SCZ-associated GRIN2A variants are predominantly LoF and offer a potential mechanism by which SCZ and DD/ID-linked variants can cause different effects on receptor function and therefore result in divergent pathological outcomes.